TY - JOUR
T1 - Discovery of benzo[g]indoles as a novel class of non-covalent Keap1-Nrf2 protein-protein interaction inhibitor
AU - Yasuda, Daisuke
AU - Yuasa, Akihiro
AU - Obata, Rika
AU - Nakajima, Mao
AU - Takahashi, Kyoko
AU - Ohe, Tomoyuki
AU - Ichimura, Yoshinobu
AU - Komatsu, Masaaki
AU - Yamamoto, Masayuki
AU - Imamura, Riyo
AU - Kojima, Hirotatsu
AU - Okabe, Takayoshi
AU - Nagano, Tetsuo
AU - Mashino, Tadahiko
N1 - Funding Information:
This work was supported by the Platform for Drug Discovery, Informatics, and Structural Life Science from the Ministry of Education, Culture, Sports, Science and Technology (MEXT), and Japan Agency for Medical Research and Development ( AMED ), 2012-2016. A
Publisher Copyright:
© 2017 Elsevier Ltd
PY - 2017/11/15
Y1 - 2017/11/15
N2 - The Keap1-Nrf2 system is an attractive target for drug discovery regarding various unmet medical needs. Only covalent inhibitors for protein-protein interaction (PPI) between Keap1 and Nrf2 to activate Nrf2 have been approved or are under clinical trials, but such electrophilic compounds lack selectivity. Therefore, specific non-covalent Keap1-Nrf2 PPI inhibitors are expected to be safer Nrf2 activators. We found a novel class of non-covalent Keap1-Nrf2 PPI inhibitor that has a benzo[g]indole skeleton and an indole-3-hydroxamic acid moiety and that exhibits significant PPI inhibitory activity. Additionally, the benzo[g]indole-3-carbohydrazide derivatives were newly prepared. The benzo[g]indole derivatives showed a stronger Keap1-Nrf2 PPI inhibitory activity than Cpd16, a previously reported non-covalent PPI inhibitor. Moreover, most of the PPI inhibitors showed a high metabolic stability in a human microsome system with a low cytotoxicity against HepG2 cell lines, which suggests that novel benzo[g]indole-type Keap1-Nrf2 PPI inhibitors are expected to be biological tools or lead compounds for Nrf2 activators.
AB - The Keap1-Nrf2 system is an attractive target for drug discovery regarding various unmet medical needs. Only covalent inhibitors for protein-protein interaction (PPI) between Keap1 and Nrf2 to activate Nrf2 have been approved or are under clinical trials, but such electrophilic compounds lack selectivity. Therefore, specific non-covalent Keap1-Nrf2 PPI inhibitors are expected to be safer Nrf2 activators. We found a novel class of non-covalent Keap1-Nrf2 PPI inhibitor that has a benzo[g]indole skeleton and an indole-3-hydroxamic acid moiety and that exhibits significant PPI inhibitory activity. Additionally, the benzo[g]indole-3-carbohydrazide derivatives were newly prepared. The benzo[g]indole derivatives showed a stronger Keap1-Nrf2 PPI inhibitory activity than Cpd16, a previously reported non-covalent PPI inhibitor. Moreover, most of the PPI inhibitors showed a high metabolic stability in a human microsome system with a low cytotoxicity against HepG2 cell lines, which suggests that novel benzo[g]indole-type Keap1-Nrf2 PPI inhibitors are expected to be biological tools or lead compounds for Nrf2 activators.
KW - High-throughput screening
KW - Keap1
KW - Metabolic stability
KW - Nrf2
KW - Protein-protein interaction inhibitor
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U2 - 10.1016/j.bmcl.2017.10.008
DO - 10.1016/j.bmcl.2017.10.008
M3 - Article
C2 - 29037947
AN - SCOPUS:85031426399
VL - 27
SP - 5006
EP - 5009
JO - Bioorganic and Medicinal Chemistry Letters
JF - Bioorganic and Medicinal Chemistry Letters
SN - 0960-894X
IS - 22
ER -